Surfaces exposed to humid and aqueous environments are readily colonized by microorganisms and may be further colonized by higher organisms. The resultant fouling has many adverse effects on these surfaces and the objects they compose. Current anti-fouling methods often involve the use of highly toxic and environmentally stable compounds, usually including a metal ion such as copper (as in CuO2) or tin (as in tri-butyltin fluoride, TBTF). Research has shown that these heavy metals remain in the environment and retain their toxicity for many years. Furthermore, it has been demonstrated that these compounds become concentrated in plants and animals higher up the food chain with many adverse effects. These compounds, while effective as anti-fouling agents are under increasing pressure from environmental regulations that seek to limit the concentration of heavy metals in the environment. An effective anti-fouling agent with a short and known biological lifetime is therefore of great interest to the industry.
This invention describes the use of poly-substituted isothiouronium salts (T1), and poly-substituted guanidinium salts (G1). The biological activity of these classes of compounds has been recognized previously as variously fungicides, bactericides, lepidoptericides, antibiotics, etc. It is also known that isothiouronium salts (T1). and neutral isothioureas (T2) can be interconverted. Similarly, the interconversion of guanidinium salts (G1) and neutral guanidines (G2) is also well established. These pairs of compounds are related as acid and conjugate base, differing only in protonation state. Consequently, in many cases the biological activity of isothiouronium salts can be inferred from the known activity of isothioureas, and vice versa. Similarly the biological activity of guanidinium salts can be inferred from the known activity of neutral guanidines, and vice versa. This is particularly true when the compounds are dispersed in an aqueous environment.
Many authors have reported examples of the activity of isothiouronium salts and isothioureas. For example, U.S. Pat. No. 4,515,813 discloses the lepidoptericidal properties of isothiourea compounds. Fungicidal and bactericidal activity of this class of compounds were also noted. compounds. Fungicidal and bactericidal activity of this class of compounds were also noted. Similarly, the use of pyridyl thiouronium salts as fungicides are disclosed in U.S. Pat. No. 3,655,898, and related pyridyl thiouronium N-oxides are useful as wood preservatives as described in Japan Patent 53109903. German Patent 2637651 describes the use of S-(p-isopropylbenzyl)thiouronium chloride as one of the biocidal components in a water-based paint formulation. Marine antifouling activity by dissolved isothioureas is disclosed in Japan Patent 05163105.
Similarly, there are many examples of the biological activity of guanidinium salts and guanidines. Several naturally occurring toxins from marine organisms contain the guanidinium functional group, most notably tetrodotoxin. The best-known commercial example is dodecyl guanidinium acetate (dodine), widely used as a fungicide and bactericide to control scab on hard fruits. It is also used as an industrial biocide and preservative. Dodine also shows synergistic anti-fouling activity in conjunction with other well-known antifouling agents such as tributyltin oxide as reported by Evans, Callow and Wood (1986). Dodine, in conjunction with quaternary ammonium salts, is reported by Bidwell, Farris and Cherry (1995) to control the growth of zebra mussles and Asian clams (moluscicidal activity). Such soluble formulations have also been disclosed in U.S. Pat. No. 4816163, U.S. Pat. No. 4906385, and Canadian Patent No. 1269927. A method to prepare an antifouling coating from a mixture of dodine and additional biocides has been disclosed in Japan Patent No. 04225945.
Most of the previously reported isothiouronium and guanidinium containing compounds are monosubstituted with a relatively low carbon-number substituent. Although this is appropriate for applications requiring soluble biocides, it is obvious to someone skilled in the art that a successful coating application in contact with water will require sparingly soluble biocides. Solubility can be limited by increasing the carbon number of a single substituent, or by increasing the number of similar sized substituents. The present invention discloses the utility of the second strategy.
A second issue, previously unrecognized, is the role that anion exchange capacity may play in biocidal activity. Prior discussion of the mode of action of biocidal formulations containing isothiouronium or guanidinium salts focussed on their detergent capabilities (references cited above). Our parallel work on the development of ion-exchange membranes for dissolved gas sensors (U.S. patent application Ser. No. 09/444,867) showed that guanidinium salts are effective agents for the exchange of hydroxide ions across membranes. In the context of biocidal activity, an anion exchanger would disrupt the normal ionic and pH balance across a cell membrane that would prove to be fatal for microorganisms.
This invention describes the synthesis of a series of poly-substituted isothiouronium of type T1 and poly-substituted guanidinium salts of type G1, via intermediate thioureas of type T3, their formulation in paints, and their activity in limiting the growth of marine organisms on the treated surfaces as a result of prolonged immersion in open seawater. In addition to the biocidal and anti-fouling activity disclosed below, compounds of types T1 and G1 posses two additional properties of significant utility. The first is that they are colorless, that is they do not absorb significant amounts of visible light. Thus they could be used to inhibit fouling on windows exposed to humid or aqueous environments. The second is that they degrade easily in a marine environment to produce benign by-products. Thus a buildup of these compounds in the environment will be avoided.
Structural Formulae
General Formulae of Compounds Discussed 